Prostate cancer (PCA), the leading cancer diagnosed among men in the United States, has a highly variable rate of progression, with indolent forms having minimal impact on functional ability and mortality while aggressive forms have high mortality. Though physical symptoms, digital rectal exam, measuring prostate-specific antigen levels, and biopsy are currently the methods of choice for detecting PCA, they are not ideal as sometimes these screening tools mistake those without disease as having disease and can not distinguish between benign and malignant disease, or slow growing versus rapidly progressing cancer. Thus PCA management requires not only improved early detection, but also the development of markers for distinct disease types as well as for predicting risk for aggressive cancer. Members of a gene family we have been studying, termed SIBLINGs (for Small Integrin Binding Ligand N-linked Glycoproteins) are normally expressed by bone but are also induced in different cancers. Initial studies indicate that SIBLINGs can be informative markers for PCA detection and that individual members correlate with different aspects of PCA initiation and progression. Because of these different pathological associations, our main hypothesis is that SIBLINGs can be developed as diagnostic and prognostic biomarkers for prostate health. An immediate objective is to provide evidence to support multi-site trials of these novel PCA biomarkers, to speed their rapid clinical evaluation. Our intermediate objective is to determine whether these proteins will enable the discrimination between different forms of prostate health/status (e.g. - normal, benign, cancerous) as well as in other cancers or diseases which share similar pathophysiology to PCA. The ultimate goal of the research is to provide new markers that either alone or in combination with existing clinical measures not only improve diagnosis, but also predict the aggressiveness of PCA so that rational treatment decisions can be made by both patients and physicians. The research approach is to use a national reference set of case-control samples for PCA, case control sets of matched samples from other disease states (e.g. - benign prostate hyperplasia, osteoporosis), and samples from a large longitudinal cohort study of aging. Central to the research is the use of samples where extensive demographic and clinical follow up data has also been collected on these subjects/samples. A sufficient number of cases (for diagnostics) and events (for prognostics) have been collected to enable a clinically meaningful testing of marker utility. SIBLINGs are measured in serum in study subjects by competitive enzyme linked immunosorbent assays and the markers are evaluated individually and in composites with other demographic and clinical parameters through appropriate and complementary statistical methods. The proposed research has the potential to validate novel serum tests that may aid accurate identification of early stage disease, reduce over treatment of slow growing disease and help identify patients with more aggressive disease requiring additional therapy.